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Pharmacological MRI responses of raclopride in rats: The relationship with D2 receptor occupancy and cataleptic behavior.
SYNAPSE ( IF 1.6 ) Pub Date : 2020-07-09 , DOI: 10.1002/syn.22180 Yukiko Masaki 1 , Yuto Kashiwagi 1 , Takemi Rokugawa 1 , Miwa Ito 1 , Hitoshi Iimori 2 , Kohji Abe 1
SYNAPSE ( IF 1.6 ) Pub Date : 2020-07-09 , DOI: 10.1002/syn.22180 Yukiko Masaki 1 , Yuto Kashiwagi 1 , Takemi Rokugawa 1 , Miwa Ito 1 , Hitoshi Iimori 2 , Kohji Abe 1
Affiliation
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Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy. To clarify these relationships, we examined receptor occupancy measurements using positron emission tomography (PET) (n = 3~5), fMRI (n = 5~8) and a cataleptic behavior (n = 6) with raclopride, a dopamine D2 receptor antagonist (8, 20, and 200 μg/kg) on Wistar rats. Dopamine D2 receptor occupancy was increased dose dependently by raclopride (41.8 ± 2.7%, 8 μg/kg; 64.9 ± 2.8%, 20 μg/kg; 83.1 ± 3.0%, 200 μg/kg). phMRI study revealed significant positive responses to raclopride at 200 μg/kg specifically in the striatum and nucleus accumbens, related to dopaminergic system. Slight fMRI responses were observed at 20 μg/kg in some areas corresponding to the striatum and nucleus accumbens. There were no noticeable fMRI responses at 8 μg/kg raclopride administration. Raclopride at 200 μg/kg significantly increased the cataleptic score, although, at 8 and 20 μg/kg, raclopride had no significant effects. These findings showed that raclopride‐induced fMRI responses were observed at doses inducing cataleptic behavior and high D2 receptor occupancy, suggesting that phMRI can be useful for dose selection in clinical trial as an evaluation method of brain activity, which reflects behavioral responses induced by target engagements.
中文翻译：
大鼠雷克必利的药理MRI反应：与D2受体的占有率和抗感性行为的关系。
药理磁共振成像（phMRI）可以使用功能性MRI（fMRI）可视化药物的大脑药理作用。phMRI可以帮助我们促进中枢神经系统（CNS）药物的开发。然而，很少有研究表明中枢神经系统药物诱导的功能磁共振成像反应与潜在靶标参与或行为功效之间的剂量关系。为了阐明这些关系，我们使用正电子发射断层扫描（PET）（n = 3〜5 ），fMRI（n = 5〜8）和感官行为（n = 6）在Wistar大鼠上使用多巴胺D2受体拮抗剂雷洛必利（8、20和200μg/ kg）。多巴胺D2受体的占用量受到雷氯必利的剂量依赖性增加（41.8±2.7％，8μg/ kg; 64.9±2.8％，20μg/ kg; 83.1±3.0％，200μg/ kg）。phMRI研究显示，以200μg/ kg的剂量对雷氯必利具有明显的阳性反应，特别是在纹状体和伏隔核中，与多巴胺能系统有关。在与纹状体和伏隔核相对应的某些区域中，以20μg/ kg的剂量观察到轻微的fMRI反应。在服用8μg/ kg raclopride时，没有明显的fMRI反应。雷卡必利的浓度为200μg/ kg时，可显着提高其感观评分，但雷卡必利的浓度分别为8和20μg/ kg时则无明显作用。
更新日期：2020-07-09
中文翻译：
大鼠雷克必利的药理MRI反应：与D2受体的占有率和抗感性行为的关系。
药理磁共振成像（phMRI）可以使用功能性MRI（fMRI）可视化药物的大脑药理作用。phMRI可以帮助我们促进中枢神经系统（CNS）药物的开发。然而，很少有研究表明中枢神经系统药物诱导的功能磁共振成像反应与潜在靶标参与或行为功效之间的剂量关系。为了阐明这些关系，我们使用正电子发射断层扫描（PET）（n = 3〜5 ），fMRI（n = 5〜8）和感官行为（n = 6）在Wistar大鼠上使用多巴胺D2受体拮抗剂雷洛必利（8、20和200μg/ kg）。多巴胺D2受体的占用量受到雷氯必利的剂量依赖性增加（41.8±2.7％，8μg/ kg; 64.9±2.8％，20μg/ kg; 83.1±3.0％，200μg/ kg）。phMRI研究显示，以200μg/ kg的剂量对雷氯必利具有明显的阳性反应，特别是在纹状体和伏隔核中，与多巴胺能系统有关。在与纹状体和伏隔核相对应的某些区域中，以20μg/ kg的剂量观察到轻微的fMRI反应。在服用8μg/ kg raclopride时，没有明显的fMRI反应。雷卡必利的浓度为200μg/ kg时，可显着提高其感观评分，但雷卡必利的浓度分别为8和20μg/ kg时则无明显作用。
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